rs139548132

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2

The NM_015836.4(WARS2):c.37T>G(p.Trp13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,944 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W13R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 22 hom. )

Consequence

WARS2
NM_015836.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:5B:2

Conservation

PhyloP100: -0.145

Variant links:

Genes affected

WARS2 (HGNC:12730): (tryptophanyl tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. This gene encodes the mitochondrial tryptophanyl-tRNA synthetase. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

WARS2 links:

WARS2-AS1 (HGNC:):

WARS2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-119140608-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3233281.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043417513).

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WARS2	NM_015836.4 linkuse as main transcript	c.37T>G	p.Trp13Gly	missense_variant	1/6	ENST00000235521.5	NP_056651.1	Q9UGM6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WARS2	ENST00000235521.5 linkuse as main transcript	c.37T>G	p.Trp13Gly	missense_variant	1/6	1	NM_015836.4	ENSP00000235521.4		Q9UGM6-1
WARS2	ENST00000369426.9 linkuse as main transcript	c.37T>G	p.Trp13Gly	missense_variant	1/6	1		ENSP00000358434.5		Q9UGM6-2

Frequencies

GnomAD3 genomes

AF:

0.00315

AC:

480

AN:

152276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00489

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00322

AC:

809

AN:

250992

Hom.:

AF XY:

0.00352

AC XY:

478

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.000695

Gnomad NFE exome

AF:

0.00436

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00363

AC:

5311

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

2703

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00418

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00369

Gnomad4 FIN exome

AF:

0.000880

Gnomad4 NFE exome

AF:

0.00398

Gnomad4 OTH exome

AF:

0.00404

GnomAD4 genome

AF:

0.00315

AC:

480

AN:

152394

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000841

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00489

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00423

Hom.:

Bravo

AF:

0.00300

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00331

AC:

402

EpiCase

AF:

0.00616

EpiControl

AF:

0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures

Pathogenic:4Uncertain:2

Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_015836.3:c.37T>G in the WARS2 gene has an allele frequency of 0.006 in other subpopulation in the gnomAD database. Functional studies demonstrate that c.37T>G has affected a mitochondrial signal peptide (SP) leading to mislocalization of the mutant protein in the cells (PMID: 28236339). It was detected in individual with autosomal recessive Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, compound heterozygous with c.325delA (PMID: 28236339). Benign computational verdict because benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3; BP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 18, 2022	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	The heterozygous p.Trp13Gly variant in WARS2 was identified by our study in the compound heterozygous state, along with another variant of unknown significance, in 1 individual with neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures. The variant has been reported in at least 7 individuals, of varied ethnicities, with neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (PMID: 29120065, 28236339, 32120303, 30831263, 31970218). This variant has been identified in 0.46% (590/128958) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs139548132) and was detected in homozygosity in 6 control individuals from various populations, suggesting that this variant is not pathogenic for neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures. This variant has also been reported in ClinVar (Variation ID: 440915) as likely benign by Invitae, pathogenic by OMIM and Institute of Human Genetics, Klinikum rechts der Isar, likely pathogenic by Reproductive Health Research and Development, BGI Genomics, and as having unknown significance by CeGaT Praxis fuer Humangenetik Tuebingen. Of the 7 affected individuals, 2 were compound heterozygotes that carried a reported likely pathogenic variants in trans and 2 were compound heterozygotes that carried variants of uncertain significance in trans which increases the likelihood that the p.Trp13Gly variant is pathogenic (Variation ID: 440914, 807717; PMID: 29120065, 28236339, 32120303, 30831263, 31970218). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 29120065, PMID: 28236339). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein. In summary, while the clinical significance of the p.Trp13Gly variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, BS2, PS3_moderate, PM3, BP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2022	- -

Parkinsonism-dystonia 3, childhood-onset

Pathogenic:2Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 20, 2021	- -

WARS2-related disorder

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 24, 2023	The WARS2 c.37T>G variant is predicted to result in the amino acid substitution p.Trp13Gly. The c.37T>G (p.Trp13Gly) variant has been described as a hypomorphic allele and reported in the compound heterozygous state in multiple unrelated families affected with intellectual disability or infantile onset leukoencephalopathy (Musante et al. 2017. PubMed ID: 28236339 ; Burke et al. 2018. PubMed ID: 29120065; Nogueira et al. 2019. PubMed ID: 30831263; Martinelli et al. 2020. PubMed ID: 32120303; Hubers et al. 2020. PubMed ID: 31970218; Skorvanek et al. 2022. PubMed ID: 34890876). In vitro study showed this variant may affect the mitochondrial localization signal (Musante et al. 2017. PubMed ID: 28236339). This variant is reported in 0.46% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 6 homozygous individuals of unknown phenotype (http://gnomad.broadinstitute.org/variant/1-119683231-A-C), and is only expected to cause disease when found in trans (on the opposite chromosome) with a second more deleterious variant in this gene (Skorvanek et al. 2022. PubMed ID: 34890876). Based on the collective evidence, we interpret this variant to be a likely pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Jan 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2024	Variant summary: WARS2 c.37T>G (p.Trp13Gly) results in a non-conservative amino acid change in the N-terminal mitochondrial signal peptide (amino acids 1-18, UniProt) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 250992 control chromosomes in the gnomAD database, including 6 homozygotes. The occurrences in homozygote controls suggest that the variant is likely benign when found in homozygous state. However, this variant (c.37T>G) has been reported in the literature in several compound heterozygous individuals affected with WARS2-Related Disorders, including patients with infantile-onset Parkinsonism (e.g. Musante_2017, Burke_2018, Nogueira_2019, Hubers_2019, Martinelli_2002, Brunet_2021, Skorvanek_2022, Schneider_2024), in addition, pathogenic variants have been confirmed in trans in the majority of these individuals and the variant has been shown to segregate with disease in related individuals. These data suggest that the pathogenicity (severity and penetrance) of the variant is genotype-dependent, i.e. highly dependent on the variant observed in trans. Several publications report experimental evidence evaluating an impact on protein function and these studies showed that the variant results in decreased (but not absent) mitochondrial localization in vitro (Musante_2017), and reduced WARS2 protein levels, with impaired mitochondrial respiratory chain activity in fibroblasts derived from compound heterozygous patients (e.g. Burke_2018, Martinelli_2020, Skorvanek_2022). The presence of homozygotes in the gnomAD control population, as well as the many compound heterozygous patients found to harbor this variant, and functional evidence collectively suggest that this variant represents a hypomorphic allele and will cause disease when in trans with another pathogenic variant but will not cause disease in homozygous state (e.g. Skorvanek_2022, Ilinca_2022). The following publications have been ascertained in the context of this evaluation (PMIDs: 33619735, 29120065, 31970218, 35074316, 32120303, 28236339, 30831263, 39073549, 34890876). ClinVar contains an entry for this variant (Variation ID: 440915). Based on the evidence outlined above, the variant represents a hypomorphic allele that is subject to interallelic interactions, which in compound heterozygous state, together with other (more severe) variants in trans, can cause WARS2-Related Disorders, therefore, this variant was classified as pathogenic. -

not provided

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28236339, 30920170, 33611074, 34890876, 32120303, 31970218, 33619735, 29120065, 30831263, 34958143, 35795805, 35872528, 33949708, 35074316, 37417438, 36539902, 37107582) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	- -

Neurodevelopmental disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 29, 2024

The p.Trp13Gly variant in WARS2 has been reported in the compound heterozygous state in >15 individuals with WARS2-associated disorders including infantile-onset parkinson's disease, dystonia and neurodevelopmental disorder. In at least 5 individuals, the p.Trp13Gly variant was identified along with another disease causing variant in WARS2 (Musante 2017 PMID: 28236339, Burke 2018 PMID: 29120065, Hubers 2019 PMID: 31970218, Nogueira 2019 PMID: 30831263, Martinelli 2020 PMID: 32120303, Brunet 2021 PMID: 33619735, Dzinovic 2022 PMID: 35872528, Gabriel 2022 PMID: 34958143, Skorvanek 2022 PMID: 34890876, Pauly 2023 PMID: 37107582). This variant segregated in 3 affected relatives from 2 families (Musante 2017 PMID: 28236339, Skorvanek 2022 PMID: 34890876). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 440915) and has been identified in 0.77% (47/6060) of Middle Eastern and 0.4% (251/60006) of Admixed Americans chromosomes including 22 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). In vitro studies provide some evidence that this variant impacts protein function by impairing mitochondrial localization and a reduction of protein level and consequently affecting mitochondrial respiratory chain activity (Musante 2017 PMID: 28236339, Burke 2018 PMID: 29120065) but computational prediction tools and conservation analyses suggest that this variant may not impact the protein. Since this variant has been identified in the homozygous state in multiple individuals in gnomAD, the variant most likely represents a hypomorphic allele and is only expected to cause disease when found in trans with a second more deleterious variant in this gene, such as a loss of function variant. It is not expected to cause disease in the homozygous state. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive WARS2 deficiency. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong, PS3_Supporting, BS4. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2021

The c.37T>G (p.W13G) alteration is located in exon 1 (coding exon 1) of the WARS2 gene. This alteration results from a T to G substitution at nucleotide position 37, causing the tryptophan (W) at amino acid position 13 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.12

Sift

Benign

0.081

T;T

Sift4G

Uncertain

0.016

D;T

Polyphen

0.0010

.;B

Vest4

0.43

MVP

0.25

MPC

0.74

ClinPred

0.037

GERP RS

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over